Substituted oxindole derivatives as tyrosine kinase inhibitors

ABSTRACT

The present invention is related to oxindole derivatives of structure (I), compositions containing the same, and methods of use and manufacture of the same. Such compounds generally are useful pharmacologically as agents in those disease states alleviated by the alteration of mitogen activated signaling pathways in general, and in particular in the inhibition or antagonism of protein kinases, which pathologically involve aberrant cellular proliferation. Such disease states include tumor growth, restenosis, atherosclerosis, pain and thrombosis, In particular, the present invention relates to a series of substituted oxindole compounds, which exhihit Trk family protein tyrosine kinase inhibition, and which are useful in cancer therapy and chronic pain indications.

BACKGROUND OF THE INVENTION

[0001] The present invention is related to oxindole derivatives,compositions containing the same, and methods of use and manufacture ofthe same. Such compounds generally are useful pharmacologically asagents in those disease states alleviated by the alteration of mitogenactivated signaling pathways in general, and in particular in theinhibition or antagonism of protein kinases, which pathologicallyinvolve aberrant cellular proliferation. Such disease states includetumor growth, restenosis, atherosclerosis, pain and thrombosis. Inparticular, the present invention relates to a series of substitutedoxindole compounds, which exhibit Trk family protein tyrosine kinaseinhibition, and which are useful in cancer therapy and chronic painindications.

[0002] Cell growth, differentiation, metabolism and function are verytightly controlled in higher eukaryotes. The ability of a cell torapidly and appropriately respond to the array of external and internalsignals it continually receives is of critical importance in maintaininga balance between these processes (Rozengurt, Current Opinion in CellBiology 1992, 4, 161-5; Wilks, Progress in Growth Factor Research 1990,2, 97-111). The loss of control over cellular regulation can often leadto aberrant cell function or death, often resulting in a disease statein the parent organism.

[0003] The protein kinases represent a large family of proteins whichplay a central role in the regulation of a wide variety of cellularprocesses and maintaining control over cellular function (Hanks, et al.,Science 1988, 241, 42-52). A partial list of such kinases includes ab1,ATK, bcr-ab1, Blk, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK4,CDK6, cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes,FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, flt-1, Fps, Frk, Fyn,Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2,ros, tie₁, tie₂, TRK,Yes, and Zap70.

[0004] One of the most commonly studied pathways involving kinaseregulation is cellular signalling from receptors at the cell surface tothe nucleus (Crews and Erikson, Cell 1993, 74, 215-7). One example ofthis pathway includes a cascade of kinases in which members of thegrowth factor receptor tyrosine kinases (such as EGF-R, PDGF-R, VEGF-R,IGF1-R, the Insulin receptor), deliver signals through phosphorylationto other kinases such as Src tyrosine kinase, and the Raf, Mek and Erkserine/threonine kinase families (Crews and Erikson, Cell 1993, 74,215-7; Ihle, et al., Trends in Biochemical Sciences 1994, 19, 222-7).Each of these kinases is represented by several family members (Pelechand Sanghera, Trends in Biochemical Sciences 1992, 17, 233-8) which playrelated, but functionally distinct roles. The loss of regulation of thegrowth factor signaling pathway is a frequent occurrence in cancer aswell as other disease states.

[0005] A variety of evidence suggests that nerve growth factor (NGF) maybe a mediator of some persistent pain states, including neuropathic andinflammatory pain. For example: a) NGF is rapidly elevated in inflamedtissues.; b) NGF specific antibodies substantially diminish inflammatoryhypersensitivity; c) injection of NGF into adult rats causes a profoundhypersensitivity to noxious heat and mechanical stimuli; and d) lowlevel administration of recombinant NGF induces hyperalgesia in healthyhumans. NGF produces hyperalgesia through several potential mechanisms.NGF results in the upregulation of peptide neurotransmitters in neuronsthat detect painful stimuli (nociceptors). NGF increases theexcitability of spinal cord neurons to activation. Mast cells expressNGF receptors and NGF triggers the release of granules containinghistamine and serotonin. Histamine and serotonin are capable ofsensitizing nociceptors. (Wood, John (2000) Pathology of Visceral Pain:Molecular Mechanisms and Therapeutic Implications II. Genetic Aproachesto Pain Therapy. Am. J. Physiol. 278(40), G507-G512.)

[0006] NGF binds to two different receptors, the neurotrophin receptorp75 (p75NTR) and TrkA. p75NTR is a member of a family of receptors thatincludes tumor necrosis factor receptor (TNFR) and FAS/APO1. Thesereceptors have in common a cysteine-rich motif in the extracellulardomain, a single transmembrane domain, and a cytoplasmic domain. p75NTRsignals in a fashion similar to TNFR and FAS via the activation of NFkB,JNK, and ceramide production. The functional significance of p75NTR inNGF mediated biological responses is not clear. Proposed functionsinclude a) modulation of TrkA driven responses and b) induction of celldeath in cells that express p75NTR, but not TrkA.

[0007] TrkA appears to be the primary mediator of NGF driven biologicalresponses. The most compelling evidence for this comes from NGF and TrkAknockout mice. Mice defective in either the ligand or receptor componentof this system have remarkably similar phenotypes. Examples of thesephenotypes include severe sensory defects characterized by a completeloss of nociceptive activity and deficiencies in thermoception.Anatomically these mice exhibit extensive peripheral nervous system cellloss in trigeminal, dorsal root, and sympathetic ganglia. Other evidencefor the involvement of TrkA in NGF driven responses comes from the studyof the PC12 cell line. PC12 cells express high levels of p75NTR andTrkA. NGF causes PC12 cells to differentiate into a neuronal phenotypecharacterized by the development of axonal projections. Loss of TrkAprevents PC12 cells from differentiating in response to NGF. (Eggert,A.; Ikegaki, N.; Lui, X.; Chou, T.; Lee, V.; Trojanowski, J. Q.;Brodeur, G. M.; (2000) Molecular Dissection of TrkA Signal TransductionPathways Mediating Differentiation in human Neuroblastoma Cells.Oncogene, 19(16), 2043-2051.)

[0008] There is evidence that Trk tyrosine kinases play a role in thedevelopment of a variety of cancers including, for example, breast andprostate cancer. (Guate, J. L. et al, (1999) Expression of p75LNGFR andTrk Neurotrophin Receptors in Normal and Neoplastic Human Prostate, BJUInt 84(4), 495-502; Tagliabue, E. et al, S. Nerve Growth Factorcooperates with p185HER2 in Activating Growth of Human Breast CarcinomaCells, (2000) J. Biol Chem. 275(8), 5388-5394). Further, there is strongevidence that mediation of the Trk kinase signaling will providebeneficial biological effects. (LeSauteur, L. et al, (1998) Developmentand Uses of Small Molecule Ligands of TrkA Receptors, Adv. Behav. Biol.49, 615-625; Zhu, Z. et al, (1999) Nerve Growth Factor ExpressionCorrelates with Perineural Invasion and Pain in Human Pancreatic Cancer,Journal of Clinical Oncology, 17(8), 2419-28; Friess, H et al, NerveGrowth Factor and its High-Affinity Receptor in Chronic Pancreatitis,(1999) Annals of Surgery 230(5), 615-24.)

[0009] TrkA is a receptor tyrosine kinase that belongs to a subfamily oftyrosine kinases that includes TrkB, and TrkC. TrkB and TrkC arestructurally similar to TrkA, but respond to different ligands in theneurotrophin family. NGF signaling through TrkA has been bestcharacterized in the PC12 system and is similar to signal transductionmechanisms of other tyrosine kinase receptors. NGF exists as ahomodimer. Binding of NGF promotes dimerization, andautophoshphorylation of TrkA. Phosphorylation of TrkA increases thecatalytic activity of the kinase domain and creates binding sites forSH2 domain containing cytoplasmic proteins. SH2 domain binding eventsinitiate the activation of several signal transduction pathways such asPLCg, ras, PI3 kinase/AKT, and Raf/MEK/ERK. (Frade, J. M. et al (1998)Nerve growth factor: two receptors, multiple functions, BioEssays 20:137-145; Kaplan, D. R. et al, (1997) Signal Transduction by theNeurotrophin Receptors, Current Opinion in Cell Biology. 9: 213-221;Barbacid, M. (1995) Neurotrophic factors and their receptors, CurrentOpinion in Cell Biology. 7:148-155; Snider, W. D. (1994) Functions ofthe Neurotrophins During Nervous System Development: What the Knockoutsare Teaching Us, Cell, 77:627-638.)

[0010] The selective inhibition of Trk family of kinases (TrkA, TrkB,and TrkC) is therefore an object of the present invention.

[0011] There is a continuing need in the medical field for new and moreeffective treatments for cancer and for the relief of pain, especiallychronic pain. Because TrkA and other Trk kinases may serve as a mediatorof NGF driven biological responses, inhibitors of TrkA and other Trkkinases may provide an effective treatment for cancer and for chronicpain states. At present, there is an unmet need for small moleculecompounds that may be readily synthesized and are potent inhibitors ofTrkA and other Trk family kinases. The present inventors have nowdiscovered novel oxindole derivative compounds that selectively inhibitthe catalytic activity of TrkA and/or other Trk family kinases therebyproviding new treatment strategies for those afflicted with cancer andchronic pain.

[0012] It is additionally possible that inhibitors of certain kinasesmay have utility in the treatment of diseases when the kinase is notmis-regulated, but is nonetheless essential for maintenance of thedisease state.

SUMMARY OF THE INVENTION

[0013] In one aspect the present invention provides, compounds of theformula (I):

[0014] wherein

[0015] X is N, CH, CCF₃, or C(C₁₋₁₂ aliphatic);

[0016] R¹ is hydrogen, C₁₋₁₂ aliphatic, thiol, hydroxy, hydroxy-C₁₋₁₂aliphatic, Aryl, Aryl-C₁₋₁₂ aliphatic, R⁶-Aryl-C₁₋₁₂ aliphatic, Cyc,Cyc-C₁₋₆ aliphatic, Het, Het-C₁₋₁₂ aliphatic, C₁₋₁₂ alkoxy, Aryloxy,amino, C₁₋₁₂ aliphatic amino, di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂aliphatic aminocarbonyl, di-C₁₋₁₂ aliphatic aminosulfonyl, C₁₋₁₂alkoxycarbonyl, halogen, cyano, sulfonamide, or nitro, where R⁶, Aryl,Cyc and Het are as defined below;

[0017] R² is hydrogen, C₁₋₁₂ aliphatic, N-hydroxyimino-C₁₋₁₂ aliphatic,C₁₋₁₂ alkoxy, hydroxy-C₁₋₁₂ aliphatic, C₁₋₁₂ alkoxycarbonyl, carboxylC₁₋₁₂ aliphatic, Aryl, R⁶-Aryl-oxycarbonyl, R⁶-oxycarbonyl-Aryl, Het,aminocarbonyl, C₁₋₁₂ aliphatic-aminocarbonyl, Aryl-C₁₋₁₂aliphatic-aminocarbonyl, R⁶-Aryl-C₁₋₁₂ aliphatic-aminocarbonyl,Het-C₁₋₁₂ aliphatic-aminocarbonyl, hydroxy-C₁₋₁₂aliphatic-aminocarbonyl, C₁₋₁₂-alkoxy-C₁₋₁₂ aliphatic-aminocarbonyl,C₁₋₁₂ alkoxy-C₁₋₁₂ aliphatic-amino, di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂aliphatic aminocarbonyl, di-C₁₋₁₂ aliphatic aminosulfonyl, halogen,hydroxy, nitro, C₁₋₁₂ aliphatic-sulfonyl, aminosulfonyl, or C₁₋₁₂aliphatic-aminosulfonyl, where Aryl and Het are as defined below;

[0018] further wherein R¹ and R² are optionally joined to form a fusedring, said fused ring selected from the group as defined for Het below,or any of said fused rings optionally substituted by C₁₋₁₂ aliphatic,halogen, nitro, cyano, C₁₋₁₂ alkoxy, carbonyl-C₁₋₁₂ alkoxy or oxo;

[0019] R³ is hydrogen, C₁₋₁₂ aliphatic, hydroxy, hydroxy C₁₋₁₂aliphatic, di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂ aliphatic aminocarbonyl,di-C₁₋₁₂ aliphatic aminosulfonyl, C₁₋₁₂ alkoxy, Aryl, Aryloxy,hydroxy-Aryl, Het, hydroxy-Het, Het-oxy, or halogen, where Aryl and Hetare as defined below;

[0020] further wherein R² and R³ are optionally joined to form a fusedring, said fused ring selected from the group as defined for Het below,or any of said fused rings optionally substituted by C₁₋₆ aliphatic orC₁₋₆ aliphatic-carbonyl;

[0021] R⁴ is sulfonic acid, C₁₋₁₂ aliphatic-sulfonyl, sulfonyl-C₁₋₁₂aliphatic, C₁₋₁₂ aliphatic-sulfonyl-C₁₋₆ aliphatic, C₁₋₆aliphatic-amino, R⁷-sulfonyl, R⁷-sufonyl-C₁₋₁₂ aliphatic,R⁷-aminosulfonyl, R⁷-aminosulfonyl-C₁₋₁₂ aliphatic, R⁷-sulfonylamino,aminosulfonyl-C₁-C₁₂-aliphatic, R⁷-sulfonylamino-C₁₋₁₂ aliphatic,aminosulfonylamino, di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂ aliphaticaminocarbonyl, di-C₁₋₁₂ aliphatic aminosulfonyl, di-C₁₋₁₂ aliphaticamino, di-C₁₋₁₂ aliphatic aminocarbonyl, di-C₁₋₁₂ aliphaticaminosulfonyl-C₁₋₁₂ aliphatic, (R⁸)₁₋₃-Arylamino, (R⁸)₁₋₃-Arylsulfonyl,(R⁸)₁₋₃-Aryl-aminosulfonyl, (R⁸)₁₋₃-Aryl-sulfonylamino, Het-amino,Het-sulfonyl, Het-aminosulfonyl, aminoiminoamino, oraminoiminoaminosulfonyl, where R⁷, R⁸, Aryl and Het are as definedbelow;

[0022] R⁵ is hydrogen;

[0023] and further wherein R⁴ and R⁵ are optionally joined to form afused ring, said ring selected from the group as defined for Het below,or any of said used rings optionally substituted by C₁₋₁₂ aliphatic, oxoor dioxo;

[0024] R⁶ is C₁₋₁₂ aliphatic, hydroxy, C₁₋₁₂ alkoxy, or halogen;

[0025] R⁷ is hydrogen, C₁₋₁₂ aliphatic, C₁₋₁₂ alkoxy, hydroxy-C₁₋₁₂alkoxy, hydroxy-C₁₋₁₂ aliphatic, carboxylic acid, C₁₋₁₂aliphatic-carbonyl, Het, Het-C₁₋₁₂-aliphatic, Het-C₁₋₁₂-alkoxy,di-Het-C₁₋₁₂-alkoxy Aryl, Aryl-C₁₋₁₂-aliphatic, Aryl-C₁₋₁₂-alkoxy,Aryl-carbonyl, C₁₋₁₈ alkoxyalkoxyalkoxyalkoxyaliphatic, or hydroxylwhere Het and Aryl are as defined below;

[0026] R⁸ is hydrogen, nitro, cyano, C₁₋₁₂ alkoxy, halo, carbonyl-C₁₋₁₂alkoxy or halo-C₁₋₁₂ aliphatic;

[0027] Aryl is phenyl, naphthyl, phenanthryl or anthracenyl; Cyc iscyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl, any one of which may have one or more degrees ofunsaturation;

[0028] Het is a saturated or unsaturated heteroatom ring system selectedfrom the group consisting of benzimidazole, dihydrothiophene, dioxin,dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan,imidazole, isoquinoline, morpholine, oxazole, oxadiazole, oxathiazole,oxathiazolidine, oxazine, oxadiazine, piperazine, piperadine, pyran,pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine,quinoline, tetrahydrofuran, tetrazine, thidiazine, thiadiazole,thiatriazole, thiazine, thiazole, thiomorpholine, thiophene, thiopyran,triazine and triazole, with the proviso that when R² is thiadiazine,then R⁴ cannot be methylsulfone;

[0029] and the pharmaceutically acceptable salts, solvates, orphysiologically functional derivatives thereof including biohydrolyzableesters, biohydrolyzable amides, biohydrolyzable carbamates solvates,hydrates, affinity reagents or prodrugs thereof in either crystalline oramorphous form.

[0030] In another aspect of the present invention, there is providedcompounds of formula (I):

[0031] wherein

[0032] X is N, CH, or C(C₁₋₆ aliphatic);

[0033] R¹ is hydrogen, C₁₋₆ aliphatic, hydroxy-C₁₋₆ aliphatic, Aryl-C₁₋₆aliphatic, R⁶-Aryl-C₁₋₆ aliphatic, Cyc-C₁₋₆ aliphatic, Het-C₁₋₆aliphatic, C₁₋₆ alkoxy, Aryloxy, aminocarbonyl, di-C₁₋₆ aliphatic amino,di-C₁₋₆ aliphatic aminocarbonyl, di-C₁₋₆ aliphatic aminosulfonyl, C₁₋₆alkoxycarbonyl, halogen, or nitro, where R⁶, Aryl, Cyc and Het are asdefined below;

[0034] R² is hydrogen, C₁₋₆ aliphatic, R⁷-C₁₋₆ aliphatic, C₁₋₆alkoxy,hydroxy-C₁₋₆ aliphatic, C₁₋₆ alkoxycarbonyl, carboxyl C₁₋₆ aliphatic,Aryl, R⁶-Aryl-oxycarbonyl, R⁶-oxycarbonyl-Aryl, Het, aminocarbonyl, C₁₋₆aliphatic-aminocarbonyl, Aryl-C₁₋₆ aliphatic-aminocarbonyl, R⁶-Aryl-C₁₋₆aliphatic-aminocarbonyl, Het-C₁₋₆ aliphatic-aminocarbonyl, hydroxy-C₁₋₆aliphatic-aminocarbonyl, C₁₋₆-alkoxy-C₁₋₆ aliphatic-aminocarbonyl, C₁₋₆alkoxy-C₁₋₆ aliphatic-amino, di-C₁₋₆ aliphatic amino, di-C₁₋₆ aliphaticaminocarbonyl, di-C₁₋₆ aliphatic aminosulfonyl, halogen, hydroxy, nitro,sulfo, C₁₋₆ aliphatic-sulfonyl, aminosulfonyl, C₁₋₆aliphatic-aminosulfonyl, or quaternary ammonium, where R⁷, Aryl and Hetare as defined below;

[0035] further wherein R¹ and R² are optionally joined to form a fusedring, said fused ring selected from the group as defined for Het above,or any of said fused rings optionally substituted by halogen or oxo;

[0036] R³ is hydrogen, C₁₋₆ aliphatic, hydroxy, hydroxy C₁₋₆ aliphatic,di-C₁₋₆ aliphatic amino, di-C₁₋₆ aliphatic aminocarbonyl, di-C₁₋₆aliphatic aminosulfonyl, C₁₋₆ alkoxy, Aryl, Aryfoxy, hydroxy-Aryl, Het,hydroxy-Het, Het-oxy, or halogen, where Aryl and Het are as definedbelow;

[0037] further wherein R² and R³ are optionally joined to form a fusedring, said fused ring selected from the group as defined for Het above,or any of said fused rings optionally substituted by C₁₋₆ aliphatic orC₁₋₆ aliphatic-carbonyl;

[0038] R⁴ is sulfonic acid, C₁₋₁₂ aliphatic-sulfonyl, sulfonyl-C₁₋₁₂aliphatic, C₁₋₁₂ aliphatic-sulfonyl-C₁₋₆ aliphatic, C₁₋₆aliphatic-amino, R⁷-sulfonyl, R⁷-sulfonyl-C₁₋₁₂ aliphatic,R⁷-aminosulfonyl, R⁷-aminosulfonyl-C₁₋₁₂ aliphatic, R⁷-sulfonylamino,R⁷-sulfonylamino-C₁₋₁₂ aliphatic, aminosulfonylamino,aminosulfonyl-C₁-C₁₂-aliphatic, di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂aliphatic aminocarbonyl, di-C₁₋₁₂ aliphatic aminosulfonyl, di-C₁₋₁₂aliphatic amino, di-C₁₋₁₂ aliphatic aminocarbonyl, di-C₁₋₁₂ aliphaticaminosulfonyl-C₁₋₁₂ aliphatic, (R⁸)₁₋₃-Arylamino, (R⁸)₁₋₃-Arylsulfonyl,(R⁸)₁₋₃-Aryl-aminosulfonyl, (R⁸)₁₋₃-Aryl-sulfonylamino, Het-amino,Het-sulfonyl, Het-aminosulfonyl, aminoiminoamino, oraminoiminoaminosulfonyl, where R⁷, R⁸, Aryl and Het are as definedbelow;

[0039] R⁵is hydrogen;

[0040] and further wherein R⁴ and R⁵ are optionally joined to form afused ring, said ring selected from the group as defined for Het above,or any of said used rings optionally substituted by oxo or dioxo;

[0041] R⁶ is hydrogen, C₁₋₆ aliphatic, hydroxy, C₁₋₆ alkoxy, or halogen;

[0042] R⁷ is hydrogen, C₁₋₁₂ aliphatic, C₁₋₁₂ alkoxy, hydroxy-C₁₋₁₂alkoxy, hydroxy-C₁₋₁₂ aliphatic, carboxylic acid, C₁₋₁₂aliphatic-carbonyl, Het, Het-C₁₋₁₂-aliphatic, Het-C₁₋₁₂-alkoxy,di-Het-C₁₋₁₂-alkoxy Aryl, Aryl-C₁₋₁₂-aliphatic, Aryl-C₁₋₁₂-alkoxy,Aryl-carbonyl, C₁₋₁₈ alkoxyalkoxyalkoxyalkoxyaliphatic,or hydroxyl whereHet and Aryl are as defined below;

[0043] R⁸ is hydrogen or halo-C₁₋₆ aliphatic;

[0044] Aryl is phenyl, or naphthyl;

[0045] Cyc is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl, any one of which may have one or more degreesof unsaturation;

[0046] Het is a saturated or unsaturated heteroatom ring system selectedfrom the group consisting of benzimidazole, dihydrothiophene, dioxin,dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan,imidazole, morpholine, oxazole, oxadiazole, oxathiazole,oxathiazolidine, oxazine, oxadiazine, piperazine, piperadine, pyran,pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine,tetrahydrofuran, tetrazine, thiadiazine, thiadiazole, thiatriazole,thiazine, thiazole, thiomorpholine, thiophene, thiopyran, triazine andtriazole with the proviso that when R² is thiadiazine, then R⁴ cannot bemethylsulfone;

[0047] and the pharmaceutically acceptable salts, solvates, orphysiologically functional derivatives thereof including biohydrolyzableesters, biohydrolyzable amides, biohydrolyzable carbamates, solvates,hydrates, affinity reagents or prodrugs thereof in either crystalline oramorphous form.

[0048] In a further aspect of the present invention, there is providedcompounds of formula (I):

[0049] wherein

[0050] X is N, CH, or CCH₃;

[0051] R¹ is hydrogen, C₁₋₆ aliphatic, hydroxy-C₁₋₆ aliphatic, di-C₁₋₆aliphatic amino, di-C₁₋₆ aliphatic aminocarbonyl, di-C₁₋₆ aliphaticaminosulfonyl, Aryl-C₁₋₆ aliphatic, R⁶-Aryl-C₁₋₆ aliphatic, Cyc-C₁₋₆aliphatic, Het-C₁₋₆ aliphatic, C₁₋₆ alkoxy, Aryloxy, aminocarbonyl, C₁₋₆alkoxycarbonyl, halogen, or nitro, where R⁶, Aryl, Cyc and Het are asdefined below;

[0052] R² is hydrogen, C₁₋₆ aliphatic, N-hydroxyimino-C₁₋₆ aliphatic,C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl, Aryl, R⁶-Aryloxycarbonyl, Het,aminocarbonyl, C₁₋₆ aliphatic aminocarbonyl, Aryl-C₁₋₆ aliphaticaminocarbonyl, R⁶-Aryl-C₁₋₆ aliphatic aminocarbonyl, Het-C₁₋₆ aliphaticaminocarbonyl, di-C₁₋₆ aliphatic amino, di-C₁₋₆ aliphatic aminocarbonyl,di-C₁₋₆ aliphatic aminosulfonyl, hydroxy-C₁₋₆ aliphatic aminocarbonyl,C₁₋₆-alkoxy-C₁₋₆ aliphatic aminocarbonyl, C₁₋₆ alkoxy-C₁₋₆ aliphaticamino, halogen, hydroxy, nitro, C₁₋₆ aliphatic sulfonyl, oraminosulfonyl, C₁₋₆ aliphatic aminosulfonyl, where Aryl and Het are asdefined below;

[0053] further wherein R¹ and R² are optionally joined to form a fusedring, said fused ring selected from the group as defined for Het below,or any of said fused rings optionally substituted by halogen or oxo;

[0054] R³ is hydrogen, C₁₋₆ aliphatic, hydroxy, hydroxy C₁₋₆ aliphatic,di-C₁₋₆ aliphatic amino, di-C₁₋₆ aliphatic aminocarbonyl, di-C₁₋₆aliphatic aminosulfonyl C₁₋₆ alkoxy, Aryloxy, Het, or halogen, whereAryl and Het are as defined below;

[0055] further wherein R² and R³ are optionally joined to form a fusedring, said fused ring selected from the group as defined for Het below,or any of said fused rings optionally substituted by C₁₋₆ alkyl or C₁₋₆alkylcarbonyl;

[0056] R⁴ is R⁷-sulfonyl, R⁷-sulfonyl C₁₋₆-aliphatic, C₁₋₆ aliphaticsulfonyl-C₁₋₆ aliphatic, R⁷-aminosulfonyl, di-C₁₋₆ aliphatic amino,di-C₁₋₆ aliphatic aminocarbonyl, di-C₁₋₆ aliphatic aminosulfonyl,di-C₁₋₆ aliphatic aminosulfonyl-C₁₋₆ aliphatic,aminosulfonyl-C₁-C₁₂-aliphatic, R⁷-aminosulfonyl C₁₋₆ aliphatic,aminosulfonylamino, R⁷-C₁₋₆ aliphatic aminosulfonyl-C₁₋₆ aliphatic,Aryl, Het, R⁸-Aryl-aminosulfonyl, Het-aminosulfonyl, oraminoiminoaminosulfonyl, where R⁷,R⁸, Aryl and Het are as defined below;

[0057] R⁵ is hydrogen;

[0058] and further wherein R⁴ and R⁵ are optionally joined to form afused ring, said ring selected from the group as defined for Het below,or any of said used rings optionally substituted by oxo or dioxo;

[0059] R⁶ is hydroxy, C₁₋₆ alkoxy, or halogen;

[0060] R⁷ is hydrogen, C₁₋₆ aliphatic, hydroxy C₁₋₆-alkoxy, hydroxy-C₁₋₆aliphatic, C₁₋₆ aliphatic carbonyl, Aryl-carbonyl, C₁₋₁₂alkoxyalkoxyalkoxyalkoxyalkyl, hydroxyl, Aryl, Aryl-C₁₋₆-alkoxy,Aryl-C₁₋₆-aliphatic, Het, Het-C₁₋₆-alkoxy, di-Het-C₁₋₆-alkoxy,Het-C₁₋₆-alkoxy, Het-C₁₋₆-aliphatic, di-Het-C₁₋₆-aliphatic;

[0061] R⁸ is trifluoromethyl;

[0062] Aryl is phenyl;

[0063] Cyc is cyclobutyl;

[0064] Het is a saturated or unsaturated heteroatom ring system selectedfrom the group consisting of benzimidazole, dihydrothiophene, dioxolane,furan, imidazole, morpholine, oxazole, pyridine, pyrrole, pyrrolidine,thiadiazole, thiazole, thiophene, and triazole, with the proviso thatwhen R² is thiadiazine, then R⁴ cannot be methylsulfone;

[0065] and the pharmaceutically acceptable salts, solvates,physiologically functional derivatives thereof, includingbiohydrolyzable esters, biohydrolyzable amides, biohydrolyzablecarbamates, solvates, hydrates, affinity reagents or prodrugs thereof ineither crystalline or amorphous form.

[0066] In a still further aspect of the present invention, there isprovided compounds of formula (I):

[0067] wherein

[0068] X is CH;

[0069] R¹ is hydrogen, C₁₋₁₂ aliphatic, thiol, hydroxy, hydroxy-C₁₋₁₂aliphatic, Aryl, Aryl-C₁₋₁₂ aliphatic, R⁶-Aryl-C₁₋₁₂ aliphatic, Cyc,Cyc-C₁₋₆ aliphatic, Het, Het-C₁₋₁₂ aliphatic, C₁₋₁₂ alkoxy, Aryloxy,amino, C₁₋₁₂ aliphatic amino, di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂aliphatic aminocarbonyl, di-C₁₋₁₂ aliphatic aminosulfonyl, C₁₋₁₂alkoxycarbonyl, halogen, cyano, sulfonamide, or nitro, where R⁶, Aryl,Cyc and Het are as defined below;

[0070] R² is hydrogen, C₁₋₁₂ aliphatic, N-hydroxyimino-C₁₋₁₂ aliphatic,C₁₋₁₂ alkoxy, hydroxy-C₁₋₁₂ aliphatic, C₁₋₁₂ alkoxycarbonyl, carboxylC₁₋₁₂ aliphatic, Aryl, R⁶-Aryl-oxycarbonyl, R⁶-oxycarbonyl-Aryl, Het,aminocarbonyl, C₁₋₁₂ aliphatic-aminocarbonyl, Aryl-C₁₋₁₂aliphatic-aminocarbonyl, R⁶-Aryl-C₁₋₁₂ aliphatic-aminocarbonyl,Het-C₁₋₁₂ aliphatic-aminocarbonyl, hydroxy-C₁₋₁₂aliphatic-aminocarbonyl, C₁₋₁₂-alkoxy-C₁₋₁₂ aliphatic-aminocarbonyl,C₁₋₁₂ alkoxy-C₁₋₁₂ aliphatic-amino, di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂aliphatic aminocarbonyl, di-C₁₋₁₂ aliphatic aminosulfonyl, halogen,hydroxy, nitro, C₁₋₁₂ aliphatic-sulfonyl, aminosulfonyl, or C₁₋₁₂aliphatic-aminosulfonyl, where Aryl and Het are as defined below;

[0071] further wherein R¹ and R² are optionally joined to form a fusedring, said fused ring selected from the group as defined for Het below,or any of said fused rings optionally substituted by halogen, nitro,cyano, C₁₋₁₂ alkoxy, carbonyl-C₁₋₁₂ alkoxy or oxo;

[0072] R³ is hydrogen, C₁₋₁₂ aliphatic, hydroxy, hydroxy C₁₋₁₂aliphatic, di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂ aliphatic aminocarbonyl,di-C₁₋₁₂ aliphatic aminosulfonyl, C₁₋₁₂ alkoxy, Aryl, Aryloxy,hydroxy-Aryl, Het, hydroxy-Het, Het-oxy, or halogen, where Aryl and Hetare as defined below;

[0073] further wherein R² and R³ are optionally joined to form a fusedring, said fused ring selected from the group as defined for Het below,or any of said fused rings optionally substituted by C₁₋₆ aliphatic orC₁₋₆ aliphatic-carbonyl;

[0074] R⁴ is R⁷-aminosulfonyl, R⁷-aminosulfonyl-C₁₋₁₂ aliphatic,R⁷-sulfonylamino, R⁷-sulfonylamino-C₁₋₁₂ aliphatic, aminosulfonylamino,di-C₁₋₁₂ aliphatic aminosulfonyl, di-C₁₋₁₂ aliphatic aminosuIfonyl-C₁₋₁₂aliphatic, (R⁸)₁₋₃-Aryl-aminosuIfonyl, aminosulfonyl-C₁-C₁₂-aliphatic,

[0075] (R⁸)₁₋₃-Aryl-sulfonylamino, or aminoiminoaminosulfonyl, where R⁷,R⁸, Aryl and Het are as defined below;

[0076] R⁵ is hydrogen;

[0077] R⁶ is C₁₋₁₂ aliphatic, hydroxy, C₁₋₁₂ alkoxy, or halogen;

[0078] R⁷ is hydrogen, C₁₋₁₂ aliphatic, C₁₋₁₂ alkoxy, hydroxy-C₁₋₁₂alkoxy, hydroxy-C₁₋₁₂ aliphatic, carboxylic acid, C₁₋₁₂aliphatic-carbonyl, Het, Het-C₁₋₁₂-aliphatic, Het-C₁₋₁₂-alkoxy,di-Het-C₁₋₁₂-alkoxy Aryl, Aryl-C₁₋₁₂-aliphatic, Aryl-C₁₋₁₂-alkoxy,Aryl-carbonyl, C₁₋₁₈ alkoxyalkoxyalkoxyalkoxyaliphatic,or hydroxyl whereHet and Aryl are as defined below;

[0079] R⁸ is hydrogen, nitro, cyano, C₁₋₁₂ alkoxy, halo, carbonyl-C₁₋₁₂alkoxy or halo-C₁₋₁₂ aliphatic;

[0080] Aryl is phenyl, naphthyl, phenanthryl or anthracenyl;

[0081] Cyc is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl, any one of which may have one or more degreesof unsaturation;

[0082] Het is a saturated or unsaturated heteroatom ring system selectedfrom the group consisting of benzimidazole, dihydrothiophene, dioxin,dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan,imidazole, morpholine, oxazole, oxadiazole, oxathiazole,oxathiazolidine, oxazine, oxadiazine, piperazine, piperadine, pyran,pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine,tetrahydrofuran, tetrazine, thiadiazine, thiadiazole, thiatriazole,thiazine, thiazole, thiomorpholine, thiophene, thiopyran, triazine andtriazole with the proviso that when R² is thiadiazine. then R⁴ cannot bemethylsulfone;

[0083] and the pharmaceutically acceptable salts, solvates,physiologically functional derivatives thereof, includingbiohydrolyzable esters, biohydrolyzable amides, biohydrolyzablecarbamates solvates, hydrates, affinity reagents or prodrugs thereof ineither crystalline or amorphous form.

[0084] In another aspect of the present invention, there is provided acompound of the formula I, or salts, solvates, or physiologicalfunctional derivatives thereof

[0085] wherein:

[0086] R¹ is hydrogen or halogen;

[0087] R² is hydrogen, hydroxy or methoxy;

[0088] R³ is hydrogen or C₁-C₆ branched alkyl;

[0089] R⁴ is selected from the group consisting of

4′-CH₂-SO₂NHCH₃, 4′-NHSO₂CH₃,

[0090] R⁵ is hydrogen; and

[0091] X is N or CH.

[0092] Due to the presence of an oxindole exocyclic double bond, alsoincluded in the compounds of the invention are their respective pure Eand Z geometric isomers as well as mixtures of E and Z isomers. Theinvention as described and claimed does not set any limiting ratios onprevalence of Z to E isomers. Thus compound number 104 in the tablesbelow is disclosed and claimed as the E geometric thereof, the Zgeometric isomer thereof and a mixture of the E and Z geometric isomersthereof, but not limited by any given ratio(s).

[0093] Likewise, it is understood that compounds of formula (I) mayexist in tautomeric forms other than that shown in the formula.

[0094] Certain of the compounds as described will contain one or morechiral, or asymmetric, centers and will therefore be capable of existingas optical isomers that are either dextrorotatory or levorotatory. Alsoincluded in the compounds of the invention are the respectivedextrorotatory or levorotatory pure preparations, and mixtures thereof.

[0095] Certain compounds of formula (I) above may exist instereoisomeric forms (e.g. they may contain one or more asymmetriccarbon atoms or may exhibit cis-trans isomerism). The individualstereoisomers (enantiomers and diastereoisomers) and mixtures of theseare included within the scope of the present invention. Likewise, it isunderstood that compounds of formula (I) may exist in tautomeric formsother than that shown in the formula and these are also included withinthe scope of the present invention.

[0096] A further aspect of the invention provides a method of treating adisorder in a mammal, said disorder mediated by inappropriate mitogenactivated kinase activity, including administering to said mammal atherapeutically effective amount of a compound of formula (I) or a salt,solvate, or physiologically functional derivative thereof. In oneembodiment, the disorder is cancer. In another embodiment the disorderis chronic pain. In a further embodiment, the disorder involves abnormalangiogenesis, such as arthritis, diabetic retinopathy, maculardegeneration and psoriasis.

[0097] In a related aspect the present invention comprises a method forinhibiting a kinase comprising bringing said kinase into contact with acompound of formula (I), or a salt, solvate, or physiologicallyfunctional derivative thereof.

[0098] Another aspect of the present invention provides for the use of acompound of formula (I), or a salt, solvate, or physiologicallyfunctional derivative thereof, in the preparation of a medicament forthe treatment of a disorder mediated by inappropriate TrkA activity. Inone embodiment, the disorder is cancer. In another embodiment, thedisorder is chronic pain. In a further embodiment, the disorder involvesabnormal angiogenesis, such as arthritis, diabetic retinopathy, maculardegeneration and psoriasis.

[0099] Additionally, compounds of formula (I) or salts, solvates, orphysiologically functional derivatives thereof, can be used in thepreparation of a medicament for the treatment of organ transplantrejection, tumor growth, chemotherapy-induced mucositis,radiation-induced mucositis, plantar-palmar syndrome,chemotherapy-induced alopecia, chemotherapy-induced thrombocytopenia,chemotherapy-induced leukopenia and hirsutism or of treating a diseasestate selected from the group consisting of: mucocitis, restenosis,atherosclerosis, rheumatoid arthritis, angiogenesis, hepatic cirrhosis,glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis,chronic obstructive pulmonary disease, thrombotic microangiopathy,aglomerulopathy, psoriasis, diabetes mellitus, inflammation, aneurodegenerative disease, macular degeneration, actinic keratosis andhyperproliferative disorders.

[0100] Another aspect of the present invention provides the use of anactive compound of formula (I), in co-administration or alternatingadministration with previously known anti-tumor therapies for moreeffective treatment of such tumors.

[0101] Other aspects of the present invention related to the inhibitionof protein kinases are discussed in more detail below.

[0102] The inappropriate TrkA activity referred to herein is any TrkAactivity that deviates from the normal TrkA activity expected in aparticular mammalian subject. Inappropriate TrkA activity may take theform of, for instance, an abnormal increase in activity, or anaberration in the timing and or control of TrkA activity. Suchinappropriate activity may result then, for example, from overexpressionor mutation of the protein kinase leading to inappropriate oruncontrolled activation. Furthermore, it is also understood thatunwanted TrkA activity may reside in an abnormal source, such as amalignancy. That is, the level of TrkA activity does not have to beabnormal to be considered inappropriate, rather the activity derivesfrom an abnormal source.

[0103] Compounds we have synthesized as part of the present inventionwhich are currently preferred are listed in Tables 1 and 2 below.Compounds are identified by the numbers shown in the first column;variables below in the rest of the columns are with reference to thegeneric structure (I). Corresponding IUPAC nomenclature are disclosed inTable 2. Since all substituents at each point of substitution arecapable of independent synthesis of each other, the tables are to beread as a matrix in which any combination of substituents is within thescope of the disclosure and claims of the invention. TABLE 1 (I)

Example R¹ R² R³ R⁴ R⁵ X 1 Cl OH i-propyl 4′-CH₂—SO₂NHCH₃ H N 2 —H H H4′-NHSO₂CH₃ H CH 3 —H H H

H CH 4 —H H H

H CH 5 —H H H 3′-SO₂NH₂ H CH

[0104] Standard accepted nomenclature corresponding to the Examples setforth in this specification are set forth below. In some casesnomenclature is given for one or more possible isomers. TABLE II Example1: {4-[(2Z)-2-(4-chloro-5-hydroxy-6-isopropyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]phenyl}-N- methylmethanesulfonamideExample 2: N-(4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}phenyl)methanesulfonamide Example 3:4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-amino}-N-(2-pyridinyl)benzenesulfonamide Example 4:N-(5-methyl-1,3,4-thiadiazol-2-yl)-4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}- benzenesulfonamide Example 5:3-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}benzenesulfonamide

[0105] The invention discloses six different points of substitution onstructural formula (I). Each of these points of substitution bears asubstituent whose selection and synthesis as part of this invention wasindependent of all other points of substitution on formula (I). Thus,each point of substitution is now further described individually.

[0106] Preferred substitutions at the R¹ position include hydrogen,halogen, amide, nitro, lower alkyl, hydroxy, hydroxyalkyl,pyrimidineloweralkyl, loweralkoxycarbonyl, cyclic loweralkyl,hydroxyphenylloweralkyl, phenoxy, alkoxy, or pyrazole, or are fused withR² to form fused thiazole, pyrazole, triazole, halogen-substituteddiazole, acyl substituted pyrrole, and pyridine, rings. Most preferredare hydrogen, halogen, methyl and fused with R² for form fused thiazoleand fused pyridine. Most highly preferred are halogen and hydrogen.

[0107] Preferred substitutions at the R² position include hydrogen,halogen, hydroxyl, sulfate, amine, quaternary amine, amide, ester,phenyl, alkoxy, aminosulfonyl, lower alkyl sulfonyl, furanyl lower alkylamide, pyridinyl lower alkyl amide, alkoxy-substituted phenyl loweralkyl amide, morpholino lower alkyl amide, imidazolyl lower alkyl amide,hydroxy lower alkyl amide, alkoxy lower alkyl amide, lower alkyl amide,lower alkyl sulfonamide, lower alkyl hydroxy substituted amino, nitro,halogen-substituted phenoxycarbonyl, or triazole or oxazole rings, orare fused with R³ to form a fused oxazole, pyrrole, or dioxolane ring,which fused rings can be substituted by lower alkyl, lower alkylcarbonyl, or, when said fused ring is a hetero ring having nitrogen asthe heteroatom, forming a quaternary ammonium salt ionically bonded witha halogen atom. Most preferred are hydrogen, hydroxyl, oxazolyl, loweralkoxy, or fused with R¹ to form fused thiazolyl or fused pyridyl Mosthighly preferred are hydroxy, methoxy and hydrogen.

[0108] Preferred substitutions at R³ include hydrogen, lower alkyl,hydroxy lower alkyl, halogen, phenoxy, and alkoxy. Most preferred arehydrogen and branched lower alkyl. Most highly preferred is hydrogen andisopropyl.

[0109] Preferred substitutions at R⁴ include sulfonylamino,sulfonylaminoamino, lower alkyl sulfonylamino, lower alkylsulfonyl loweralkyl, alkoxysulfonylamino, phenylcarbonylsulfonylamino,phenoxysulfonyl, hydroxy lower alkylsulfonylamino, hydroxy loweralkylsulfonylamino lower alkyl, alkyl, phenylsulfonylamino, optionallysubstituted by halogen substituted lower alkyl, aminoiminosulfonylamino,alkylsulfonylaminoalkyl, pyridinyl lower alkyl sulfonylamino,benzamideazolesulfonylamino, pyridylsulfonylamino,pyrimidinylsulfonylamino, thiadiazolylsulfonylamino optionallysubstituted by lower alkyl, thiazolesulfonylamino,-aminosulfonyl-C₁-C₁₂-aliphatic, hydroxyalkoxyalkylsulfonylamino, or thegroup 4′-SO₂NH[(CH₂)₂O]₄CH₃, or are fused with R⁵ to form a fusedimidazole, triazole, cyclic sulfonylamino or thiaphene ring optionallydisubstituted on the sulfur heteroatom by oxo. The most preferredsubstitutions are 2 pyridine sulfonylamino, 4 pyridine sulfonylamino,hydroxy n-butyl sulfonylamino, methylsulfonylaminomethylene,sulfonyldimethylamino, fused 1, 2, 3-triazole, and sulfonylamino. Mosthighly preferred is 2 pyridine sulfonylamino, 4 pyridine sulfonylaminoand hydroxy n-butyl sulfonylamino. In an alternate highly preferredembodiment, R4 is 4′-CH₂-SO₂NHCH₃, 4′-NHSO₂CH₃,

[0110] or 3′-SO₂NH₂;

[0111] The preferred substitution at R⁵ is hydrogen.

[0112] Preferred substitutions at X include N, CH, and CCH₃. Mostpreferred is N and CH.

[0113] Preferred individual compounds of the present invention includeany one of the following compounds:

DETAILED DESCRIPTION OF THE INVENTION

[0114] Salts encompassed within the term “pharmaceutically acceptablesalts” refer to non-toxic salts of the compounds of this invention whichare generally prepared by reacting the free base with a suitable organicor inorganic acid or by reacting the acid with a suitable organic orinorganic base. Representative salts include the following salts:Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate,Borate, Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride,Clavulanate, Citrate, Diethanolamine, Dihydrochloride, Edetate,Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate,Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine,Hydrobromide, Hydrocloride, Hydroxynaphthoate, Iodide, Isethionate,Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate,Metaphosphoric, Methylbromide, Methylnitrate, Methylsulfate,Monopotassium Maleate, Mucate, Napsylate, Nitrate, N-methylglucamine,Oxalate, Pamoate (Embonate), Palmitate, Pantothenate,Phosphate/diphosphate, Polygalacturonate, Potassium, Salicylate, Sodium,Stearate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate,Trifluoroacetate, Triethiodide, Trimethylammonium and Valerate.

[0115] Other salts which are not pharmaceutically acceptable may beuseful in the preparation of compounds of formula (I) and these form afurther aspect of the invention.

[0116] Also included within the scope of the invention are theindividual isomers of the compounds represented by formula (I) above aswell as any wholly or partially equilibrated mixtures thereof. Thepresent invention also covers the individual isomers of the compoundsrepresented by formula above as mixtures with isomers thereof in whichone or more chiral asymmetric centers are inverted.

[0117] As used herein, the term “aliphatic” refers to the terms alkyl,alkylene, alkenyl, alkenylene, alkynyl, and alkynylene.

[0118] As used herein, the term “lower” refers to a group having betweenone and six carbons.

[0119] As used herein, the term “alkyl” refers to a straight or branchedchain hydrocarbon having from one to twelve carbon atoms, optionallysubstituted with substituents selected from the group consisting oflower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionallysubstituted by alkyl, carboxy, carbamoyl optionally substituted byalkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano,halogen, or lower perfluoroalkyl, multiple degrees of substitution beingallowed. Examples of “alkyl” as used herein include, but are not limitedto, n-butyl, n-pentyl, isobutyl, and isopropyl, and the like.

[0120] As used herein, the term “alkylene” refers to a straight orbranched chain divalent hydrocarbon radical having from one to tencarbon atoms, optionally substituted with substituents selected from thegroup consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl,lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “alkylene” as used hereininclude, but are not limited to, methylene, ethylene, and the like.

[0121] As used herein, the term “alkenyl” refers to a hydrocarbonradical having from two to ten carbons and at least one carbon-carbondouble bond, optionally substituted with substituents selected from thegroup consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl,lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed.

[0122] As used herein, the term “alkenylene” refers to a straight orbranched chain divalent hydrocarbon radical having from two to tencarbon atoms and one or more carbon-carbon double bonds, optionallysubstituted with substituents selected from the group consisting oflower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionallysubstituted by alkyl, carboxy, carbamoyl optionally substituted byalkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano,halogen, or lower perfluoroalkyl, multiple degrees of substitution beingallowed. Examples of “alkenylene” as used herein include, but are notlimited to, ethene-1,2-diyl, propene-1,3-diyl, methylene-1,1-diyl, andthe like.

[0123] As used herein, the term “alkynyl” refers to a hydrocarbonradical having from two to ten carbons and at least one carbon-carbontriple bond, optionally substituted with substituents selected from thegroup consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl,lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbarnoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed.

[0124] As used herein, the term “alkynylene” refers to a straight orbranched chain divalent hydrocarbon radical having from two to tencarbon atoms and one or more carbon-carbon triple bonds, optionallysubstituted with substituents selected from the group consisting oflower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionallysubstituted by alkyl, carboxy, carbamoyl optionally substituted byalkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano,halogen, or lower perfluoroalkyl, multiple degrees of substitution beingallowed. Examples of “alkynylene” as used herein include, but are notlimited to, ethyne-1,2-diyl, propyne-1,3-diyl, and the like.

[0125] As used herein, the term “cycloaliphatic” refers to the termscycloalkyl, cycloalkylene, cycloalkenyl, cycloalkenylene, cycloalkynyland cycloalkylnylene.

[0126] As used herein, “cycloalkyl” refers to a alicyclic hydrocarbongroup with one or more degrees of unsaturation, having from three totwelve carton atoms, optionally substituted with substituents selectedfrom the group consisting of lower alkyl, lower alkoxy, loweralkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, carbamoyloptionally substituted by alkyl, aminosulfonyl optionally substituted byalkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degreesof substitution being allowed. “Cycloalkyl” includes by way of examplecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, orcyclooctyl, and the like.

[0127] As used herein, the term “cycloalkylene” refers to annon-aromatic alicyclic divalent hydrocarbon radical having from three totwelve carbon atoms, optionally substituted with substituents selectedfrom the group consisting of lower alkyl, lower alkoxy, loweralkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, carbamoyloptionally substituted by alkyl, aminosulfonyl optionally substituted byalkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degreesof substitution being allowed. Examples of “cycloalkylene” as usedherein include, but are not limited to, cyclopropyl-1,1-diyl,cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl,cyclohexyl-1,4-diyl, cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, andthe like.

[0128] As used herein, the term “cycloalkenyl” refers to a substitutedalicyclic hydrocarbon radical having from three to twelve carbon atomsand at least one carbon-carbon double bond in the ring system,optionally substituted with substituents selected from the groupconsisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “cycloalkenylene” as used hereininclude, but are not limited to, 1-cyclopentene-3-yl,1-cyclohexene-3-yl, 1-cycloheptene-4-yl, and the like.

[0129] As used herein, the term “cycloalkenylene” refers to asubstituted alicyclic divalent hydrocarbon radical having from three totwelve carbon atoms and at least one carbon-carbon double bond in thering system, optionally substituted with substituents selected from thegroup consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl,lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “cycloalkenylene” as used hereininclude, but are not limited to, 4,5-cyclopentene-1,3-diyl,3,4-cyclohexene-1,1-diyl, and the like.

[0130] As used herein, the term “heteroatom ring system” refers to theterms heterocyclic, heterocyclyl, heteroaryl, and heteroarylene.Non-limiting examples of such heteroatom ring systems are recited in theSummary of the Invention, above.

[0131] As used herein, the term “heterocyclic” or the term“heterocyclyl” refers to a three to twelve-membered heterocyclic ringhaving one or more degrees of unsaturation containing one or moreheteroatomic substitutions selected from S, SO, SO₂, O, or N, optionallysubstituted with substituents selected from the group consisting oflower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionallysubstituted by alkyl, carboxy, carbamoyl optionally substituted byalkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano,halogen, or lower perfluoroalkyl, multiple degrees of substitution beingallowed. Such a ring may be optionally fused to one or more of another“heterocyclic” ring(s) or cycloalkyl ring(s). Examples of “heterocyclic”include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane,1,3-dioxane, piperidine, pyrrolidine, morpholine, tetrahydrothiopyran,tetrahydrothiophene, and the like.

[0132] As used herein, the term “heterocyclylene” refers to a three totwelve-membered heterocyclic ring diradical having one or more degreesof unsaturation containing one or more heteroatonis selected from S, SO,SO₂, O, or N, optionally substituted with substituents selected from thegroup consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl,lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Such a ring may be optionally fused to oneor more benzene rings or to one or more of another “heterocyclic” ringsor cycloalkyl rings. Examples of “heterocyclylene” include, but are notlimited to, tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl,pyran-2,4-diyl, 1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl,piperidine-2,4-diyl, piperidine-1,4-diyl, pyrrolidine-1,3-diyl,morpholine-2,4-diyl, and the like.

[0133] As used herein, the term “aryl” refers to a benzene ring or to anoptionally substituted benzene ring system fused to one or moreoptionally substituted benzene rings to form anthracene, phenanthrene,or napthalene ring systems, optionally substituted with substituentsselected from the group consisting of lower alkyl, lower alkoxy, loweralkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy,heteroaroyloxy, alkoxyearbonyl, nitro, cyano, halogen, lowerperfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitutionbeing allowed. Examples of aryl include, but are not limited to, phenyl,2-naphthyl, 1-naphthyl, biphenyl, and the like.

[0134] As used herein, the term “arylene” refers to a benzene ringdiradical or to a benzene ring system diradical fused to one or moreoptionally substituted benzene rings, optionally substituted withsubstituents selected from the group consisting of lower alkyl, loweralkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl,oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyloptionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy,aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lowerperfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitutionbeing allowed. Examples of “arylene” include, but are not limited to,benzene-1,4-diyl, naphthalene-1,8-diyl, anthracene-1,4-diyl, and thelike.

[0135] As used herein, the term “heteroaryl” refers to a five- toseven-membered aromatic ring, or to a polycyclic heterocyclic aromaticring, containing one or more nitrogen, oxygen, or sulfur heteroatoms atany position, where N-oxides and sulfur monoxides and sulfur dioxidesare permissible heteroaromatic substitutions, optionally substitutedwith substituents selected from the group consisting of lower alkyl,lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, loweralkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted byalkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl,aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl,acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano,halogen, lower perfluoroalkyl, heteroaryl, or aryl, multiple degrees ofsubstitution being allowed. For polycyclic aromatic ring systems, one ormore of the rings may contain one or more heteroatoms. Examples of“heteroaryl” used herein are furan, thiophene, pyrrole, imidazole,pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole,thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine,quinoline, isoquinoline, benzofuran, benzothiophene, indole, andindazole, and the like.

[0136] As used herein, the term “heteroarylene” refers to a five- toseven-membered aromatic ring diradical, or to a polycyclic heterocyclicaromatic ring diradical, containing one or more nitrogen, oxygen, orsulfur heteroatoms, where N-oxides and sulfur monoxides and sulfurdioxides are permissible heteroaromatic substitutions, optionallysubstituted with substituents selected from the group consisting oflower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionallysubstituted by alkyl, carboxy, tetrazolyl, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,alkoxycarbonyl, nitro, cyano, halogen, lower perfluoroalkyl, heteroaryl,or aryl, multiple degrees of substitution being allowed. For polycyclicaromatic ring system diradicals, one or more of the rings may containone or more heteroatoms. Examples of “heteroarylene” used herein arefuran-2,5-diyl, thiopliene-2,4-diyl, 1,3,4-oxadiazole-2,5-diyl,1,3,4-thiadiazole-2,5-diyl, 1,3-thiazole-2,4-diyl,1,3-thiazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl,pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl, and thelike.

[0137] As used herein, the term “alkoxy” refers to the group R_(a)O—,where R_(a) is aliphatic.

[0138] As used herein, the term “alkylsulfanyl” refers to the groupR_(a)S—, where R_(a) is aliphatic.

[0139] As used herein, the term “alkylsulfenyl” refers to the groupR_(a)S(O)—, where R_(a) is aliphatic.

[0140] As used herein, the term “alkylsulfonyl” refers to the groupR_(a)SO₂—, where R_(a) is aliphatic.

[0141] As used herein, the term “acyl” refers to the group R_(a)C(O)—,where R_(a) is aliphatic, cycloaliphatic, or heterocyclyl.

[0142] As used herein, the term “aroyl” refers to the group R_(a)C(O)—,where R_(a) is aryl.

[0143] As used herein, the term “heteroaroyl” refers to the groupR_(a)C(O)—, where R_(a) is heteroaryl.

[0144] As used herein, the term “alkoxycarbonyl” refers to the groupR_(a)OC(O)—, where R_(a) is aliphatic.

[0145] As used herein, the term “acyloxy” refers to the groupR_(a)C(O)O—, where R_(a) is aliphatic, cycloaliphatic, or heterocyclyl.

[0146] As used herein, the term “aroyloxy” refers to the groupR_(a)C(O)O—, where R_(a) is aryl.

[0147] As used herein, the term “heteroaroyloxy” refers to the groupR_(a)C(O)O—, where R_(a) is heteroaryl.

[0148] As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both conditions.

[0149] As used herein, the term “substituted” refers to substitutionwith the named substituent or substituents, multiple degrees ofsubstitution being allowed.

[0150] As used herein, the terms “contain” or “containing” can refer toin-line substitutions at any position along the above-defined alkyl,alkenyl, alkynyl or cycloalkyl substituents with one or more of any ofO, S, SO, SO₂, N, or N-alkyl, including, for example, —CH₂—O—CH₂—,—CH₂—SO₂—CH₂—, —CH₂—NH—CH₃ and so forth.

[0151] As used herein, the term “solvate” is a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula (I)) and a solvent. Such solvents for the purpose of theinvention may not interfere with the biological activity of the solute.Solvents may be, by way of example, water, ethanol, or acetic acid.

[0152] As used herein, the term “physiologically functional derivative”refers to any pharmaceutically acceptable derivative of a compound ofthe present invention, for example, an ester or an amide, which uponadministration to a mammal is capable of providing (directly orindirectly) a compound of the present invention or an active metabolitethereof. Such derivatives are clear to those skilled in the art, withoutundue experimentation, and with reference to the teaching of Burger'sMedicinal Chemistry And Drug Discovery, 5^(th) Edition, Vol 1:Principles and Practice, which is incorporated herein by reference tothe extent that it teaches physiologically functional derivatives.Included within the scope of the term are the terms “biohydrolyzablecarbonate”, “biohydrolyzable ureide”, “biohydrolyzable carbamate”,“biohydrolyzable ester”, and “biohydrolyzable amide”.

[0153] As used herein, the terms “biohydrolyzable carbonate”,“biohydrolyzable ureide” and “biohydrolyzable carbamate” is a carbonate,ureide, or carbamate, respectively of a drug substance (in thisinvention, a compound of general formula (I) which either a) does notinterfere with the biological activity of the parent substance butconfers on that substance advantageous properties in vivo such asduration of action, onset of action, and the like, or b) is biologicallyinactive but is readily converted in vivo by the subject to thebiologically active principle. The advantage is that, for example, thebiohydrolyzable carbamate is orally absorbed from the gut and istransformed to (I) in plasma. Many examples of such are known in the artand include by way of example lower alkyl carbamates.

[0154] As used herein, the term “biohydrolyzable ester” is an ester of adrug substance (in this invention, a compound of general formula (I)which either a) does not interfere with the biological activity of theparent substance but confers on that substance advantageous propertiesin vivo such as duration of action, onset of action, and the like, or b)is biologically inactive but is readily converted in vivo by the subjectto the biologically active principle. The advantage is that, forexample, the biohydrolyzable ester is orally absorbed from the gut andis transformed to (I) in plasma. Many examples of such are known in theart and include by way of example lower alkyl esters, loweracyloxy-alkyl esters, lower alkoxyacyloxyalkyl esters, alkoxyacyloxyesters, alkyl acylamino alkyl esters, and choline esters.

[0155] As used herein, the term “biohydrolyzable amide” is an amide of adrug substance (in this invention, a compound of general formula (I)which either a) does not interfere with the biological activity of theparent substance but confers on that substance advantageous propertiesin vivo such as duration of action, onset of action, and the like, or b)is biologically inactive but is readily converted in vivo by the subjectto the biologically active principle. The advantage is that, forexample, the biohydrolyzable amide is orally absorbed from the gut andis transformed to (I) in plasma. Many examples of such are known in theart and include by way of example lower alkyl amides, α-amino acidamides, alkoxyacyl amides, and alkylaiminoalkylcarbonyl amides.

[0156] As used herein, the term “prodrug” includes biohydrolyzableamides, biohydrolyzable esters and biohydrolyzable carbamates and alsoencompasses a) compounds in which the biohydrolyzable functionality insuch a prodrug is encompassed in the compound of formula (I): forexample, a lactam formed by a carboxylic group in R₁ and an amine in R₂,and compounds which may be oxidized or reduced biologically at a givenfunctional group to yield drug substances of formula (I). Examples ofthese functional groups are, but are not limited to,1,4-dihydropyridine, N-alkylcarbonyl-1,4-dihydropyridine,1,4-cyclohexadiene, tert-butyl, and the like.

[0157] As used herein, the term “affinity reagent” is a group attachedto the compound of formula (I) which does not affect its in vitrobiological activity, allowing the compound to bind to a target, yet sucha group binds strongly to a third component allowing a) characterizationof the target as to localization within a cell or other organismcomponent, perhaps by visualization by fluorescence or radiography, orb) facile separation of the target from an unknown mixture of targets,whether proteinaceous or not proteinaceous. An example of an affinityreagent according to b) would be biotin either directly attached to (I)or linked with a spacer of one to 50 atoms selected from the groupconsisting of C, H, O, N, S, or P in any combination. An example of anaffinity reagent according to a) above would be fluorescein, eitherdirectly attached to (I) or linked with a spacer of one to 50 atomsselected from the group consisting of C, H, O, N, S, or P in anycombination.

[0158] The term “effective amount” means that amount of a drug orpharmaceutical agent that will elicit the biological or medical responseof a tissue, system, animal or human that is being sought by aresearcher or clinician. The term “therapeutically effective amount”means any amount which, as compared to a corresponding subject who hasnot received such amount, results in improved treatment, healing,prevention, or amelioration of a disease or disorder, or a decrease inthe rate of advancement of a disease or disorder, and also includesamounts effective to enhance normal physiological function.

[0159] Whenever the terms “aliphatic” or “aryl” or either of theirprefixes appear in a name of a substituent (e.g. arylalkoxyaryloxy) theyshall be interpreted as including those limitations given above for“aliphatic” and “aryl”. Aliphatic or cycloalkyl substituents shall berecognized as being term equivalents to those having one or more degreesof unsaturation. Designated numbers of carbon atoms (e.g. C₁₋₁₀) shallrefer independently to the number of carbon atoms in an aliphatic orcyclic aliphatic moiety or to the aliphatic portion of a largersubstituent in which the term “aliphatic” appears as a prefix (e.g.“al-”).

[0160] As used herein, the term “disubstituted amine” or “disubstitutedamino-” shall be interpreted to include either one or two substitutionson that particular nitrogen atom.

[0161] As used herein, the term “oxo” shall refer to the substituent ═O.

[0162] As used herein, the term “halogen” or “halo” shall includeiodine, bromine, chlorine and fluorine.

[0163] As used herein, the term “mercapto” shall refer to thesubstituent —SH.

[0164] As used herein, the term “carboxy” shall refer to the substituent—COOH.

[0165] As used herein, the term “cyano” shall refer to the substituent—CN.

[0166] As used herein, the term “aminosulfonyl” shall refer to thesubstituent —SO₂NH₂.

[0167] As used herein, the term “carbamoyl” shall refer to thesubstituent —C(O)NH₂.

[0168] As used herein, the term “sulfanyl” shall refer to thesubstituent —S—.

[0169] As used herein, the term “sulfenyl” shall refer to thesubstituent —S(O)—.

[0170] As used herein, the term “sulfonyl” shall refer to thesubstituent —S(O)₂—.

PHARMACEUTICAL FORMULATION AND DOSES

[0171] While it is possible that, for use in therapy, therapeuticallyeffective amounts of a compound of formula I, as well as salts, solvatesand physiological functional derivatives thereof, may be administered asthe raw chemical, it is possible to present the active ingredient as apharmaceutical composition. Accordingly, the invention further providespharmaceutical compositions which include therapeutically effectiveamounts of compounds of the formula I and salts, solvates andphysiological functional derivatives thereof, and one or morepharmaceutically acceptable carriers, diluents, or excipients. Thecompounds of the formula I and salts, solvates and physiologicalfunctional derivatives thereof, are as described above. The carrier(s),diluent(s) or excipient(s) must be acceptable in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof. In accordance with another aspectof the invention there is also provided a process for the preparation ofa pharmaceutical formulation including admixing a compound of theformula I, or salts, solvates and physiological functional derivativesthereof, with one or more pharmaceutically acceptable carriers, diluentsor excipients.

[0172] The compounds of the present invention can be administered insuch oral (including buccal and sublingual) dosage forms as tablets,capsules (each including timed release and sustained releaseformulations), pills, powders, granules, elixirs, tinctures,suspensions, syrups and emulsions. Likewise, they may also beadministered in nasal, ophthalmic, otic, rectal, topical, intravenous(both bolus and infusion), intraperitoneal, intraarticular, subcutaneousor intramuscular inhalation or insufflation form, all using forms wellknown to those of ordinary skill in the pharmaceutical arts.

[0173] The dosage regimen utilizing the compounds of the presentinvention is selected in accordance with a variety of factors includingtype, species, age, weight, sex and medical condition of the patient;the severity of the condition to be treated; the route ofadministration; the renal and hepatic function of the patient; and theparticular compound or salt thereof employed. An ordinarily skilledphysician or veterinarian can readily determine and prescribe theeffective amount of the drug required to prevent, counter or arrest theprogress of the condition.

[0174] Oral dosages of the present invention, when used for theindicated effects, will range between about 0.1 to 100 mg/kg of bodyweight per day, and particularly 1 to 10 mg/kg of body weight per day.Oral dosage units will generally be administered in the range of from 1to about 250 mg and more preferably from about 25 to 250 mg. The dailydosage for a 70 kg mammal will generally be in the range of about 70 mgto 7 grams of a compound of formula I or II.

[0175] While the dosage to be administered is based on the usualconditions such as the physical condition of the patient, age, bodyweight, past medical history, route of administrations, severity of theconditions and the like, it is generally preferred for oraladministration to administer to a human. In some cases, a lower dose issufficient and, in some cases, a higher dose or more doses may benecessary. Topical application similarly may be once or more than onceper day depending upon the usual medical considerations. Advantageously,compounds of the present invention may be administered in a single dailydose, or the total daily dosage may be administered in divided doses oftwo, three or four times daily. The compounds of the invention can beprepared in a range of concentrations for topical use of 0.5 to 5 mg/mlof suitable solvent. A preferred volume for application to the scalp is2 ml, resulting in an effective dosage delivered to the patient of 1 to10 mg. For treatment of chemotherapy-induced alopecia, administration 1to 2 times prior to chemotherapy administration would be preferred, withadditional applications administered as needed. A similar regimen can bepursued for treatment of alopecia induced by radiation therapy.Furthermore, preferred compounds for the present invention can beadministered in intranasal form via topical use of suitable intranasalvehicles, or via transdermal routes, using those forms of transdermalskin patches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

[0176] In the methods of the present invention, the compounds hereindescribed in detail can form the active ingredient, and are typicallyadministered in admixture with suitable pharmaceutical diluents,excipients or carriers (collectively referred to herein as “carrier”materials) suitably selected with respect to the intended form ofadministration, that is, oral tablets, capsules, elixirs, syrups and thelike, and consistent with conventional pharmaceutical practices.

[0177] For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing and coloringagent can also be present.

[0178] Capsules are made by preparing a powder mixture as describedabove, and filling formed gelatin sheaths. Glidants and lubricants suchas colloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

[0179] Moreover, when desired or necessary, suitable binders,lubricants, disintegrating agents and coloring agents can also beincorporated into the mixture. Suitable binders include starch, gelatin,natural sugars such as glucose or beta-lactose, corn sweeteners, naturaland synthetic gums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

[0180] Oral fluids such as solution, syrups and elixirs can be preparedin dosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additive such aspeppermint oil or saccharin, and the like can also be added.

[0181] Where appropriate, dosage unit formulations for oraladministration can be microencapsulated. The formulation can also beprepared to prolong or sustain the release as for example by coating orembedding particulate material in polymers, wax or the like.

[0182] The compounds of the present invention can also be administeredin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine or phosphatidylcholines.

[0183] Compounds of the present invention may also be delivered by theuse of monoclonal antibodies as individual carriers to which thecompound molecules are coupled. The compounds of the present inventionmay also be coupled with soluble polymers as targetable drug carriers.Such polymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

[0184] The present invention includes pharmaceutical compositionscontaining 0.01 to 99.5%, more particularly, 0.5 to 90% of a compound ofthe formula (II) in combination with a pharmaceutically acceptablecarrier.

[0185] Parenteral administration can be effected by utilizing liquiddosage unit forms such as sterile solutions and suspensions intended forsubcutaneous, intramuscular or intravenous injection. These are preparedby suspending or dissolving a measured amount of the compound in anon-toxic liquid vehicle suitable for injection such as aqueousoleaginous medium and sterilizing the suspension or solution.

[0186] Alternatively, a measured amount of the compound is placed in avial and the vial and its contents are sterilized and sealed. Anaccompanying vial or vehicle can be provided for mixing prior toadministration. Non-toxic salts and salt solutions can be added torender the injection isotonic. Stabilizers, preservations andemulsifiers can also be added.

[0187] Rectal administration can be effected utilizing suppositories inwhich the compound is admixed with low-melting water-soluble orinsoluble solids such as polyethylene glycol, cocoa butter, higher esteras for example flavored aqueous solution, while elixirs are preparedthrough myristyl palmitate or mixtures thereof.

[0188] Topical formulations of the present invention may be presentedas, for instance, ointments, creams or lotions, eye ointments and eye orear drops, impregnated dressings and aerosols, and may containappropriate conventional additives such as preservatives, solvents toassist drug penetration and emollients in ointments and creams. Theformulations may also contain compatible conventional carriers, such ascream or ointment bases and ethanol or oleyl alcohol for lotions. Suchcarriers may be present as from about 1% up to about 98% of theformulation. More usually they will form up to about 80% of theformulation.

[0189] For administration by inhalation the compounds according to theinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebulizer, with the use of asuitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane,heptafluoropropane, carbon dioxide or other suitable gas. In the case ofa pressurized aerosol the dosage unit may be determined by providing avalve to deliver a metered amount. Capsules and cartridges of e.g.gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of a compound of the invention and a suitablepowder base such as lactose or starch.

[0190] The preferred pharmaceutical compositions are those in a formsuitable for oral administration, such as tablets and liquids and thelike and topical formulations.

[0191] The compounds of formula (I) can be prepared readily according tothe following reaction General Synthesis Scheme (in which all variablesare as defined before) and Examples or modifications thereof usingreadily available starting materials, reagents and conventionalsynthesis procedures. In these reactions, it is also possible to makeuse of variants which are themselves known to those of ordinary skill inthis art, but are not mentioned in greater detail.

[0192] The most preferred compounds of the invention are any or all ofthose specifically set forth in these examples. These compounds are not,however, to be construed as forming the only genus that is considered asthe invention, and any combination of the compounds or their moietiesmay itself form a genus. The following examples further illustratedetails for the preparation of the compounds of the present invention.Those skilled in the art will readily understand that known variationsof the conditions and processes of the following preparative procedurescan be used to prepare these compounds. All temperatures are degreesCelsius unless noted otherwise. g = grams mg = milligrams L = liters mL= milliliters M = molar N = normal mM = millimolar i.v. = intravenousp.o. = per oral s.c. = subcutaneous Hz = hertz mol = moles mmol =millimoles mbar = millibar psi = pounds per square inch rt = roomtemperature min = minutes h = hours mp = melting point TLC = thin layerchromatography R_(f) = relative TLC mobility MS = mass spectrometry NMR= nuclear magnetic resonance spectroscopy APCI = atmospheric pressurechemical ionization ESI = electrospray ionization m/z = mass to chargeratio t_(r) = retention time Pd/C = palladium on activated carbon ether= diethyl ether MeOH = methanol EtOAc = ethyl acetate TEA =triethylamine DIEA = diisopropylethylamine THF = tetrahydrofuran DMF =N,N-dimethylformamide DMSO = dimethylsulfoxide DDQ =2,3-dichloro-5,6-dicyano-1,4-benzoquinone LAH = lithium aluminum hydrideTFA = trifluoroacetic acid LDA = lithium diisopropylamide THP =tetrahydropyranyl NMM = N-methylmorpholine,4-methylmorpholine HMPA =hexamethylphosphoric triamide DMPU = 1,3-dimethypropylene urea d = daysppm = parts per million kD = kiloDalton LPS = lipopolysaccharide PMA =phorbol myristate acetate SPA = scintillation proximity assay EDTA =ethylenediamine tetraacetic acid FBS = fetal bovine serum PBS =phosphate buffered saline solution BrdU = bromodeoxyuridine BSA = bovineserum albumin FCS = fetal calf serum DMEM = Dulbecco's modified Eagle'smedium pfu = plaque forming units MOI = multiplicity of infection

[0193] Reagents are commercially available or are prepared according toprocedures in the literature. The physical data given for the compoundsexemplified is consistent with the assigned structure of thosecompounds. ¹H NMR spectra were obtained on VARIAN Unity Plus NMRspectrophotometers at 300 or 400 Mhz. Mass spectra were obtained onMicromass Platform II mass spectrometers from Micromass Ltd. Altrincham,UK, using either Atmospheric Chemical Ionization (APCI) or ElectrosprayIonization (ESI). Analytical thin layer chromatography (TLC) was used toverify the purity of some intermediates which could not be isolated orwhich were too unstable for full characterisation, and to follow theprogress of reactions. Unless otherwise stated, this was done usingsilica gel (Merck Silica Gel 60 F254). Unless otherwise stated, columnchromatography for the purification of some compounds, used Merck Silicagel 60 (230-400 mesh), and the stated solvent system under pressure.

[0194] General Procedures:

[0195] Procedure A—Representative Method for 1H-indol-2,3-dione (isatin)formation: Preparation of 6-H-1-thia-3,6-diaza-as-indacen-7,8-dione.

[0196] To a 1-L flask was added a magnetic stir bar, 85 g of sodiumsulfate, and 100 mL of water. The mixture was magnetically stirred untilall the solids were dissolved. To the resultant aqueous solution wasadded a solution of 6-aminobenzothiazole (4.96 g, 33.0 mmol) in 50 mL of1N aqueous hydrochloric acid and 10 mL of ethanol. The mixture wasstirred, and chloral (6.0 g, (36 mmol) was added. To the resultantsolution was added a solution of hydroxyl amine hydrochloride (7.50 g,108 mmol) in 30 mL of water. The final mixture was heated with stirringto a gentle boil until all solids dissappeared, and heating wascontinued for an additional 15 min. The flask was removed from the heat,and the solution was poured onto 500 g of ice. The mixture was stirredas the product precipatated from solution. The precipatate was collectedby suction filtration, washed thoroughly with water, filtered, and airdried to provide 6.9 g (94%) ofN-benzothiazol-6-yl-2-hydroxyimino-acetamide: ¹H NMR (DMSO-d₆): δ12.2(s, 1H), 10.4 (s, 1H), 9.2 (s, 1H), 8.5 (s, 1H), 7.9 (d, 1H), 7.7 (m,1H), 7.7 (s, 1H); APCI-MS m/z 220 (M−H)⁻. To a 1-L 3-neck round bottomflask was placed a magnetic stir bar and 100 ml of concentrated sulfuricacid. The flask was fitted with a thermometer to monitor the temperatureof the reaction. The sulfuric acid was heated to 100° C., and 10.0 g(45.2 mmol) of N-benzothiazol-6-yl-2-hydroxyimino-acetamide was addedslowly. The solution was heated for ˜1 h, and the reaction mixture waspoured into 750 g of ice and water. The residual reaction mixture in thereaction vessel was washed out with an additional 20 mL of cold water.The aqueous slurry was stirred for about 1 h and filtered. The solid waswashed thoroughly with water, filtered, and air dried to yield 4.3 g(46%) of 6-H-1-thia-3,6-diaza-as-indacen-7.8-dione: ¹H NMR(DMSO-d₆):11.1 (s, 1H), 9.2 (s, 1H), 8.2 (d, 1H), 7.0 (d, 1H); APCI-MSm/z 203 (M−H)⁻.

EXAMPLE 1 Preparation of{4-[(2Z)-2-(4-chloro-5-hydroxy-6-isopropyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]phenyl}-N-methylmethanesulfonamide

[0197]

[0198] 4-Chloro-5-hydroxy-6-I-propyl-1H-indole-2,3-dione was preparedfrom 3-chloro-4-hydroxy-5-I-propylaniline according to Procedure A.Condensation of 4-chloro-5-hydroxy-6-I-propyl-1H-indole-2,3-dione (1equivalent) with 4-hydrazino-N-methyl-benzylsulfonamide (1.1 equivalent)was heated in EtOH to 80 C. for 1 h. Upon cooling H₂O was added and thesolid was collected by vacuum filtration and dried in a vacuum oven at60 C. to afford the title compound. Electrospray MS 436 (MH⁺).

EXAMPLE 2 Preparation ofN-(4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}phenyl)methanesulfonamide

[0199]

[0200] The title compound was prepared analogous to Example 5 from3-(hydroxymethylene)-1,3-dihydro-2H-indol-2-one (0.164 g, 1.02 mmol) andN-(4-aminophenyl)-methanesulfonamide [53250-82-1, 0.186 g, 1.0 mmol] toprovide a yellow solid (0.249 g). 1H NMR (DMSO) 10.67 (d, 1H); 10.45 (s,1H); 9.56 (s, 1H); 8.50 (d, 1H); 7.52 (d, 1H); 7.35 (d, 2H); 7.18 (d,2H); 6.95 (m, 1H); 6.89 (m, 1H); 6.80 (m, 1H); 2.92 (s, 3H). MP>250.APCI (−ve) 328. Analytical Calculated for C₁₆H₁₅N₃O₃S: C, 58.35; H,4.59; N, 12.76; S, 9.73. Found: C, 58.40; H, 4.63; N, 12.75; S, 9.63.

EXAMPLE 3 Preparation of 4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methy]amino}-N-(2-pyridinyl)benzenesulfonamide

[0201]

[0202] The title compound was prepared analogous to Example 5 from3-(hydroxymethylene)-1,3-dihydro-2H-indol-2-one and sulfapyridine.Electrospray MS 393 (MH⁺).

EXAMPLE 4 Preparation ofN-(5-methyl-1,3,4-thiadiazol-2-yl)-4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}benzenesulfonamide

[0203]

[0204] The title compound was prepared analogous to Example 5 from3-(hydroxymethylene)-1,3-dihydro-2H-indol-2-one and4-amino-N-(5-methyl[1,3,4]thiadiazol-2-yl)-benzenesulfonamide. ¹H NMR(DMSO) 13.90 (bs, 1H); 10.84 (d, 1H); 10.58 (s, 1H); 8.62 (d, 1H); 7.81(d, 2H); 7.60 (d, 1H); 7.55 (d, 2H); 7.12 (m, 1H); 6.95 (m, 1H); 7.84(d, 1H); 2.48 (s, 3H). Electrospray MS 414 (MH⁺).

EXAMPLE 5 Preparation of3-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}benzenesulfonamide

[0205]

[0206] A mixture of 0.161 g (1.0 mmol) of(3Z)-3-(hydroxymethylene)-1,3-dihydro-2H-indol-2-one^(1,2) and0.180 g(1.05 mmol) of 3-aminobenzene-1-sulfonamide in 5 ml of EtOH was heatedto 80° C. for 45 min. After cooling to ambient temperature, the solidwas collected by vacuum filtration and air dried to afford3-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)-methyl]amino}benzenesulfonamideas a yellow solid (0.25 g, 79%). mp>250° C.; ¹H NMR (DMSO-d₆): 6.82 (d,J=7.7 Hz, 1H), 6.87-6.94 (m, 1H), 6.97-7.30 (m,1H), 7.35 (s, 2H),7.42-7.47 (m, 1H), 7.50-7.63 (m, 3H), 7.75 (t, J=1.8 Hz, 1H), 8.59 (d,J=12.1 Hz, 1H), 10.53 (s, 1H), 10.85 (d, J=12.3 Hz, 1H); APCI-MS: m/z316 (m+H)⁺. Anal. Calcd for C₁₅H₁₃N₃O₃S: C, 57.13; H, 4.16; N, 13.32; S,10.17. Found: C, 57.01; H, 4.23; N, 13.30; S, 10.11.

[0207] (1) Wolfbeis, Otto S.; Junek, Hans. Diacylenamines and -enoles,III. Formylation of CH2-acidic compounds via the anilinomethylenederivatives. Z. Naturforsch., B: Anorg. Chem., Org. Chem. (1979),34B(2), 283-9 (2) Winn, Martin; Kyncl, John J. Aminomethylene oxindoles.U.S. (1979), 6 pp. U.S. Pat. No. 4,145,422

[0208] Note: One equivalent of strong acid, e.g., HCl or methanesulfonicacid, is generally required in this reaction. The acid can be suppliedas the aniline salt or as a separate component. Similar conditions canbe used for condensing anilines with 3-dimethylaminomethylene-,3-t-butoxymethylene-, and 3-hydroxymethylene-substituted2,3-dihydro-1H-indol-2-ones.

BIOLOGICAL DATA

[0209] The compounds of the present invention have valuablepharmacologic properties. Different compounds from this class areparticularly effective at inhibiting the trkA kinase enzyme atconcentrations which range from 0.0001 to 1 μM and additionally showspecificity relative to other kinases. Substrate phosphorylation assayswere carried out as follows:

[0210] Screening format: Tyrosine kinase activity is being measuredusing a synthetic peptide substrate. The enzyme is a GST-fusion of theintracellular domain expressed in SF9 cells. The enzyme is expressed andpurified by Regeneron. The enzyme is preincubated with cold ATP and Mgto allow autophosphorylation prior to running the screen. This increasesthe initial rate of catalysis approximately 3 fold. The assay isperformed in 96 well microtitre plates, and reaction products aredetected following filtration through millipore p81 phosphocelluloseplates.

[0211] Assay Conditions Peptide substrate Src peptide,NH2-RRRAAAEEIYGEI-NH2 Peptide Km 60 uM ATP Km 30 uM Kcat/Km (peptide): 1× 10⁴ Assay conditions 20-40 nM TrkA, 30 uM ATP, 50 uM Src peptide, 50mM MOPS pH 7.5, 10 mM MgCl², 0.6 uCi ³³P

ATP Incubation RT for 120′ Termination Add 100 ul of 0.5% Phosphoricacid. Spot 100 ul onto millipore p81 96 well filter plate. Filter, wash3× with 200 ul 0.5% phosphoric acid. Add 50 ul scintillation cocktail.Count in Packard Topcount

[0212] Representative results are shown in Table 1 for the TrkA tyrosinekinase inhibition TABLE 1 Substrate Phosphorylation Example TrkA 1 +++ 2+++ 3 ++ 4 ++ 5 ++ IC₅₀ values Symbol <0.010 uM +++ 0.010-0.10 uM ++0.10-1.0 uM + >1.0 uM − Not determined ND

UTILITY OF INVENTION

[0213] Inhibitors of members of the TrK family of kinases find utilityas agents in the treatment of a wide variety of disorders. These includecancers and pain.

[0214] While the invention has been described and illustrated withreference to certain preferred embodiments thereof, those skilled in theart will appreciate that various changes, modifications andsubstitutions can be made therein without departing from the spirit andscope of the invention. For example, effective dosages other than thepreferred dosages as set forth herein above may be applicable as aconsequence of variations in the responsiveness of the mammal beingtreated for cancer conditions, or for other indications for thecompounds of the invention as indicated above. Likewise, the specificpharmacologic responses observed may vary according to and dependingupon the particular active compound selected or whether there arepresent certain pharmaceutical carriers, as well as the type offormulation and mode of administration employed, and such expectedvariations or differences in the results are contemplated in accordancewith the objects and practices of the present invenion. It is intended,therefore, that the invention be limited only by the scope of the claimswhich follow and that such claims be interpreted as broadly as isreasonable.

We claim:
 1. A compound of the formula I:

or salts, solvates, or physiological functional derivatives thereofwherein: R¹ is hydrogen or halogen; R² is hydrogen, hydroxy or methoxy;R³ is hydrogen or C₁-C₆ branched alkyl; R⁴ is selected from the groupconsisting of 4′-CH₂—SO₂NHCH₃, 4′-NHSO₂CH₃,

or 3′-SO₂NH₂; R⁵ is hydrogen; and X is N or CH.
 2. A compound selectedfrom the group:{4-[(2Z)-2-(4-chloro-5-hydroxy-6-isopropyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]phenyl}-N-methylmethanesulfonamide;N-(4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}phenyl)methanesulfonamide;4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}-N-(2-pyridinyl)benzenesulfonamide;N-(5-methyl-1,3,4-thiadiazol-2-yl)-4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}benzenesulfonamide;3-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}benzenesulfonamide,and salts, solvates or physiologically functional derivatives thereof.3. A pharmaceutical composition, comprising: a therapeutically effectiveamount of a compound as claimed in claim 1 or 2, or a salt, solvate, ora physiologically functional derivative thereof and one or more ofpharmaceutically acceptable carriers, diluents and excipients.
 4. Amethod of treating a disorder in a mammal, said disorder being mediatedby inappropriate TrkA activity, comprising: administering to said mammala therapeutically effective amount of a compound as claimed in claim 1or 2, or salt, solvate, or a physiologically functional derivativethereof.
 5. The method of claim 4, wherein the disorder is pain.
 6. Themethod of claim 4, wherein the disorder is cancer.
 7. A compound asclaimed in claim 1 or 2, or a salt, solvate, or a physiologicallyfunctional derivative thereof for use in therapy.
 8. Use of a compoundas claimed in claim 1 or 2, or a salt, solvate, or a physiologicallyfunctional derivative thereof in the preparation of a medicament for usein the treatment of a disorder mediated by inappropriate TrkA activity.9. The use of claim 8, wherein the disorder is pain.
 10. The use ofclaim 8, wherein the disorder is cancer.
 11. A method of treating painin a mammal, comprising: administering to said mammal a therapeuticallyeffective amount of a compound as claimed in claim 1 or 2, or a salt,solvate, or a physiologically functional derivative thereof.
 12. Amethod of treating cancer in a mammal, comprising: administering to saidmammal a therapeutically effective amount of a compound as claimed inclaims 1 or 2, or a salt, solvate, or a physiologically functionalderivative thereof.
 13. A method of treating a disorder in a mammal,said disorder being mediated by inappropriate mitogen activated kinaseactivity, comprising: administering to said mammal a therapeuticallyeffective amount of a compound as claimed in claim 1 or 2 or a salt,solvate, or physiologically functional derivative thereof.
 14. Themethod of claim 13, wherein the disorder is pain.
 15. The method ofclaim 13, wherein the disorder is cancer.